The overall goal of this project is to define the glia phenotype that promotes the establishment of neurodegenerative disease states. The proposed experiments will establish a detailed understanding of age-related changes in glial activation states and how they are influenced by a neuroinflammatory stimulus. The primary focus of these studies is the interaction of microglia with neurons. Cross-talk among brain cells may be key for the understanding of inflammatory mechanisms involved in pathogenesis of neurodegenerative diseases. Subtle micro-environmental alterations can induce microglia to react rapidly, change morphology and acquire an array of functions, including phagocytosis and the secretion of inflammatory molecules. The consequences of this activation must be tightly regulated because both inadequate and excessive responses can result in pathological consequences. The balance of these processes, operating across a time scale of decades, are carefully orchestrated and regulated until, due to normal aging, there is a gradual shift to a non-equilibrium state that is permissive for neurodegenerative processes. Aim 1 will determine the time course and regional changes in phenotype profile of the microglial activation associated with normal aging or the intraventricular infusion of LPS using a series of markers that discriminate pro- or anti-inflammatory microglia states. Aim 2 will investigate three specific mechanisms by which neurons regulate the microglial cytokine profile, the response of these mechanisms to challenge by LPS and how they are altered by normal aging. Aim 3 will examine the ability of caffeine to restore cytokine balance and promote an anti-inflammatory cytokine profile in young and aged male rats and improve spatial memory. Aim 4 will investigate the consequences of inflammation-induced alterations in NMDA-type glutamate receptor- dependent calcium ion signaling. We hypothesize that the pattern of these changes, and the degenerative changes that subsequently develop, may be due to regional variations in the micro-environment that are a direct consequence of the ability of activated microglia or injured neurons to release pro- and anti-inflammatory molecules in response to their age and ability to communicate with neurons.